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Genetic counseling: Alpha Thalassemia
Alpha Thalassemia Overview of Hemoglobin *Hemoglobin is the protein in blood that carries oxygen and gives blood its red color *A hemoglobin molecule contains four globin chains *There are different types of globin chains *One of the chains is designated alpha and the others can be grouped together and called non-alpha *The combination of two alpha chains and two non-alpha chains produces a complete hemoglobin molecule *The combination of two alpha chains and two gamma chains form "fetal" hemoglobin, termed "hemoglobin F" *Fetal hemoglobin is the primary hemoglobin in the developing fetus (With the exception of the first 10 to 12 weeks after conception. *The combination of two alpha chains and two beta chains form "adult" hemoglobin, also called "hemoglobin A". Although hemoglobin A is called "adult", it becomes the predominate hemoglobin within about 18 to 24 weeks of birth. *Must have the right amount of each type of globin being made if there is an imbalance this will result in thalassemia *There are different types of thalassemia *The severity and type of thalassemia depends on which genes are afffected *The type that we will be talking about is alpha thalassemia because it results when there is not enough alpha globin being made by the cells Alpha Globin *The genes that tell the cell how to make alpha globin are found on chromosome 16 *Each chromosome 16 has two alpha globin genes that are next to each other on the chromosome *Since each cell has two copies of chromosomes 16, a total of four alpha globin genes are usually present in each cell *There are several different possible outcomes depending on how many of these copies are not functioning (usually due to being deleted) Silent Carrier *If one of the four copies of the alpha globin gene is not present in an individual they will not have any symptoms because they still make enough alpha globin. *This individual is often referred to as a silent carrier Alpha Thalassemia Trait *If two of the genes are not present than the person is said to have the alpha thalassemia trait. *Does not cause health problems or symptoms *The red blood cells are often small and this is referred to as microcytosis *2 ways of having alpha thalassemia trait which can become important when you want to determine risks to potential children *2 genes on same chromosome not functioning (cis) figure 3 *1 gene on each chromosome (trans) figure 4 Hemoglobin H Disease *When there are three missing copies of the gene then there is even less alpha globin *This causes more serious anemia which often requires transfusions *Other symptoms include: jaundice, enlarged spleen, and increased risk of infection *Called hemoglobin H disease because of an abnormal hemoglobin that forms from excess beta globin(excess beta globin is present and 4 of these come together instead of having 2 alpha globin chains) *Hemoglobin H does not carry oxygen and damages the membrane that surrounds the red cell, accelerating cell destruction. *The combination of the very low production of alpha chains and destruction of red cells in hemoglobin H disease produces a severe, life-threatening anemia HB Bart's Hydrops Fetalis *If there are no genes present than the effects are even more serious *Often the fetus is stillborn or dies shortly after birth *Rarely, problem is detected in utero, if the disorder occured in an earlier child. In utero blood transfusions have saved some of these children. These patients require life-long transfusions and other medical support. How does the screening test determine which category a baby fits? *Newborn screening test done in Utah since Sep 2001 measures the percentage of different types of hemoglobins *Barts hemoglobin consists of 4 gamma globin chains (results from not enough alpha globin to pair up with to form the fetal hemoglobin consisting of 2 alpha and 2 gamma) (gamma globin is no longer made about 18-24 wks after birth) *Depending on how much Barts hemoglobin an infant has will help categorize them *Less than 5% -- most likely missing one gene and will be silent carrier *5-10% usually indicates loss of 2 genes and will have alpha thalassemia trait *>10% (usually 15-20%) will have more severe form Testing *Testing can be performed to determine the parents' risks for future pregnancies. A primary care physician can order the following blood tests. **complete blood count (CBC) - a measurement of size, number, and maturity of different blood cells in a specific volume of blood. **hemoglobin electrophoresis with A2 and F quantitation - differentiation of the types of hemoglobin present **FEP (free-erythrocyte protoporphyrin) and ferritin - to exclude iron deficiency anemia. *The above testing is fairly inexpensive and covered by most types of insurance *Gene testing also available, but more expensive and usually not needed *FISH can be performed to determine if there is a large deletion on chromosome 16 in the presence of severe developmental delay Types of mutations *Most are deletions of the gene(s) *About 5% of alpha thalassemia is due to point mutations *Often cause more severe thalassemia than single gene deletions *Hemoglobin Constant Spring -- most common point mutation *Stop codon mutated results in large alpha globin protein (RNA unstable and little protein is made) *Mutations have also been found in regions of DNA that regulate expression of alpha globin gene Hydrops Fetalis *Can be due to a number of different reasons (immune response to blood that is incompatible such as Rh incompatibility or nonimmune hydrops) *Nonimmune hydrops includes a number of explanations like cardiovascular, chromosome abnormality, pulmonary infection and homozygous alpha thalassemia (4 copies of alpha globin gene missing has even been seen in some with 3 missing copies) *Sometimes the reason can not be determined *Treatment for hydrops caused by some is starting to become available *Prognosis still is poor How common is Alpha thalassemia *Occurs in people of all ethnic backgrounds *More common in Mediterranean, African, and South-east Asian populations *Individuals of African descent are more likely to be silent carriers or have alpha thalassemia trait *Individuals in Southeast Asia are more likely to have all four possibilities (estimates of carrier frequency are 1/30) *Carrier frequency in other populations is not certain Rare cases of learning difficulties have been associated with alpha thalassemia (not very likely to be the case in_____) but is something that we wanted to make you aware of so that if you notice delays in her development we can see her again to follow up with her. *Some due to large deletions of chromosome 16 (other genes presumably deleted too that cause learning difficulties) *If you start to notice *Can also be due to mutation of gene XH2 (DNA helicase/repair enzyme) not clear why it causes alpha thalassemia and this is X-linked so very very unlikely Types of mutations *Most are deletions *About 5% of alpha thalassemia is due to point mutations *Often cause more severe thalassemia than single gene deletions *Hemoglobin Constant Spring -- most common point mutation *Stop codon mutated results in large alpha globin protein (RNA unstable and little protein is made) *Mutations have also been found in regions of DNA that regulate expression of alpha globin gene Are you planning more children? *May want to consider testing for you and husband in the future so that it can be determined if there are risks for future pregnancies A simple blood test can be performed that will detect most types of thalassemia trait *We will have this information in letter so when and if you want to have the testing your physician can order it *May be potential risks to _____ offspring *Keep this in mind because she may decide with her partner to have him tested Psychosocial concerns *may be nervous and think there is something serious *may be a lot of information to understand at once so talk about letter *guilt about passing on something *concern that other pregnancy with hydrops is related to this *help understand that other reasons for hydrops are more likely due to their ethnic background Websites *http://www.hopkinsmedicine.org/dnadiagnostic/alphadel.htm *http://www.emory.edu/WHSC/GENETICSLAB/dna/alpha.htm *http://sickle.bwh.harvard.edu/hbsynthesis.html *http://www.lpch.org/HealthLibrary/ChildrensHealthAZ/hematology/thalapth.htm *-- basic information about hemoglobin *-- great patient literature References *Giardina P, Hilgartner M. Update on thalassemia. Pediatr Rev 1992;13:55-62. *Rund, D Rachmilewitz, E. Thalassemia major 1995: older patients, new therapies. Blood Rev 1995; 9:25-32 *Piomelli S, Loew T. Management of thalassemia major (Cooley's anemia). Hematol Oncol Clin North Am 1991;5:557-69. *The Metabolic and Molecular Bases of Inherited Disease (8th edition). 2001. McGraw Hill. Chapter 181 Hemoglobinopathies . Weatherall, D.J., Clegg, J.B., Higgs, D.R., Wood, W.G. *Guideline: The laboratory diagnosis of haemoglobinopathies. British Journal of Haematology. 1998. 101 (783-792) Notes The information in this outline was last updated in 2002. Material obtained under GFDL Licence from http://en.wikibooks.org/wiki/Handbook_of_Genetic_Counseling